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In 1989, Olney et al. discovered that neuronal vacuolation and other cytotoxic changes ("lesions") occurred in brains of rats administered NMDA antagonists, including PCP, MK-801 (dizocilpine) and ketamine.[2] Examination of neurons in the posterior cingulate and retrosplenial cortices by electron micrograph revealed apparent lytic breakdown of mitochondria in the large vacuoles which had become apparent 2 hours after administration of an NMDA antagonist. After administration of 1.0 (mg/kg sc) MK-801 to rats, these neurotoxic changes became more apparent until about 12 hours post-dose, but the morphology of most cells appeared normal by light microscope about 24 hours post-dose. With 10 (mg/kg sc) doses of MK-801, the vacuolation reaction was still visible by light microscope 48 hours post-dose. After repeated doses of the NMDA antagonists MK-801 and PCP, the vacuolation reaction appeared consistent with the reaction after a single dose, so there was no evidence of a cumulative neurotoxic effect or that the reaction proceeded to an irreversible stage with repeated doses. The lowest doses of ketamine and tiletamine that produced neurotoxic changes visible by light microscope 4 hours post dose were 40 (mg/kg sc) and 10 (mg/kg sc), respectively. The potency of the drugs in producing these neurotoxic changes corresponded with their potency as NMDA antagonists: i.e. MK-801 > PCP > tiletamine > ketamine.

Researcher Roland N. Auer conducted similar studies to look at the correlation between age and sex and the development of NMDA receptor antagonist neurotoxicity in test rats. Older rats experienced a much higher mortality rate after the development of NAN. Female rats were found, at all ages, to have a higher incidence of necrotic (dead) neurons as a result of NAN.[3]

Dextromethorphan, a common antitussive often found in cough medicines, has been shown to cause vacuolization in rats' brains when administered at doses of 75 mg/kg.[5] However, oral administration of dextromethorphan hydrobromide (DXM HBr) to female rats in single doses as high as 120 mg/kg did not result in detectable neurotoxic changes at 4–6 hours or 24–26 hours post-dose (female rats are more sensitive to NMDA antagonist neurotoxicity).[6] The same researchers also found no evidence of neurotoxic changes in retrosplenial or cingulate cortices of male rats orally administered up to 400 mg/(kg day) DXM HBr or female rats orally administered 120 mg/(kg day) DXM HBr, both for 30 days. Carliss et al. (2007) also found that rats administered 9 mg/(kg day sc) (+)-MK-801 hydrogen maleate for 30 days did produce detectable vacuolation as expected. When 30 mg/(kg ip) dextrorphan was administered to male rats, neurotoxic changes were observed only 30 minutes post-dose.[7]

Even if the hypothesis of gross neural apoptosis proves to be false in humans, NMDA antagonists certainly have potential to permanently alter synaptic structure due to effects upon long term potentiation, which NMDA plays a crucial role in. Perhaps, with repeated usage, this would manifest, due to tolerance, thus downregulation, of the NMDA receptor system. This could feasibly alter the function/relationship of various structures, specifically the ventral visual stream, which is a likely cause of the anecdotal reports of hallucinogen persisting perception disorder (HPPD) from such chronic users.

Olney's Lesions have not yet been proven or disproven to manifest in humans. No tests have been conducted to test the validity of post-dissociative development of vacuolization in human brain tissue, and critics claim that animal testing is not a reliable predictor of the effects of dissociative substances on humans:

The evidence is that ketamine and many other NMDA-receptor antagonists that have been tested in humans, cause an acute disturbance in neural circuitry that leads to psychotic manifestations. These same drugs cause the same disturbance in neural circuitry in rats and when we look at their brains we see evidence for physical neuronal injury. Since no one has looked at the brains of humans immediately after administering these drugs, we do not know whether the physical neuronal injury occurs.[8]

In 2003, Cliff Anderson, a researcher and critic, wrote an article that illustrated that the tests conducted by Olney and Farber did not provide any conclusive evidence that lesions develop in human brains after exposure to dissociatives.[8] Anderson quoted Karl L. R. Jansen's book, Ketamine: Dreams and Realities, which cites unpublished studies on monkey brains. White's opinion that DXM caused Olney's Lesions therefore came under fire. Jansen writes:

“

Roland Auer injected monkeys with MK801 and was unable to produce any vacuoles.[...]

[R]ats have rates of brain metabolism that are almost twice as high as those in humans to start with. It is because of this higher base rate of metabolism that ketamine causes over-excitement in rats at doses below those at which it activates shutdown systems.

Frank Sharp also works in this area. I discussed with Sharp how this issue stood in 1998. His view was that reversible toxic changes in the rat started to appear at 40mg/kg and reached a level at which no further changes occurred (a plateau) at 100mg/kg, when a little cell death could be seen - but matters would not progress beyond this point. Extensive attempts to produce toxic changes in monkeys had been a total failure at doses up to 10mg/kg i.m. These monkey studies are unpublished.

I sought the view of Olney's colleague, Nuri Farber. The work of his team indicated that N-P receptors must be blocked for at least 2 hours to cause reversible changes, and at least 24 hours to produce some cell death, in rats. [...][H]e thought that the methods used in monkey studies so far were unsatisfactory, because the animals were probably too young. Only adult rats show the toxic changes. He was not prepared to accept a clean bill of health for the drug in primates until this work with older monkeys had been done, and until the drug companies published their monkey studies to support their claims of harmlessness.

There is thus no published evidence at this time (January 2000) that ketamine can produce toxic cell changes in monkeys. The unpublished monkey data that we know about, that of Frank Sharp, actually shows that there is no damage at doses up to 10mg/kg.

White therefore concluded that based on some fundamental differences between rat biology and human biology and because there have only been very few studies done on the occurrence of Olney's lesions, no connection can currently be proved or disproved.[13]